Squamous cell carcinomas of the lung and head and neck are common and highly lethal cancers for which there are no approved targeted therapies associated with a genetic biomarker. Our previous studies have nominated Fibroblast Growth Factor Receptors (FGFRs) as candidate therapeutic targets in these diseases, though clinical activity of FGFR inhibitors has been modest to date despite a few cases of dramatic response. This goal of this proposal is to develop optimized strategies for the use of FGFR inhibitors in squamous cell carcinomas, in which amplification, mutation and translocation of FGFR genes are common. The long-term objective is to enable the successful clinical application of FGFR-targeted therapies in squamous cell cancers given the urgent need to introduce effective therapies for these diseases. This proposal is unique in that it leverages extensive and novel resources at the Dana-Farber Cancer Institute/Harvard Cancer Center and incorporates the study of cancer cell lines, transgenic mouse models, patient-derived xenografts, novel FGFR antagonists and patient specimens from ongoing clinical trials of FGFR inhibitors. The proposed Specific Aims are to: 1) Evaluate known and novel recurrent FGFR alterations for oncogenicity and FGFR inhibitor sensitivity using cell line and mouse models, 2) Develop strategies to overcome acquired resistance to FGFR kinase inhibition, and 3) Define the genomic context of FGFR kinase alterations and co-dependencies in cancer cell lines and patient specimens and evaluate strategies to target co-dependencies. These studies will define which somatic FGFR alterations identified in patients with squamous cell carcinomas are the most likely to be therapeutic targets through the development and characterization of cellular model systems, transgenic animals and patient-derived xenografts. For FGFR alterations validated to confer sensitivity to FGFR inhibitors we will use cellular and murine models and tumor specimens from subjects on clinical trials of FGFR inhibitors to identify mechanisms of acquired resistance and develop strategies to overcome resistance. In cases in which oncogenic FGFR alterations do not confer sensitivity to FGFR inhibition we will identify the genomic events accounting for primary resistance and utilize cellular and animal model systems to define approaches to overcome resistance by targeting co-dependencies. Through these Aims we intend to define the optimal ways in which to apply FGFR inhibitors clinically with the ultimate goal of improving outcomes for patients with squamous cell carcinomas.